With the x-ray analysis of the structures of several serine proteases now at high resolution, it is possible to carry out detailed studies of the active sites of these enzymes. The object of the proposed research is to study the interaction of small molecules such as inhibitors or virtual substrates with proteases in order to provide information about binding modes, recognition sites and the mechanisms of enzymatic catalysis. One goal is to correlate the reactivity of enzymes with substrates and inhibitors in solution with the structure of the crystalline enzyme as observed by x-ray crystallography. This allows us to design and synthesize more effective inhibitors for use in the treatment of diseases such as emphysema. The two types of inhibitors being investigated are aza-amino acid derivatives (peptide carbazates) and peptide chloromethyl ketones. Inhibitors for the acid protease from Rhizopus Chinesis are also being synthesized in order to map the substrate binding site of this protease. BIBLIOGRAPHIC REFERENCES: "Inhibition of Human Leukocyte Elastase by Peptide Chloromethyl Ketones", P.M. Tuhy and J.C. Powers, FEBS Letters, 50, 359 (1975). "Reaction of Acyl Carbazates with Proteolytic Enzymes", J.C. Powers and D.L. Carroll, Biochem. Biophys. Res. Comm., 67, 639 (1975).